Rasmussen Shauna A, Seemiller Madelyn M, Smith Ingrid, Wilson Madeleine, Daenzer Jennifer M I, Wiggins Keenan, Fridovich-Keil Judith L
Department of Human Genetics, Emory University School of Medicine Emory University Atlanta Georgia USA.
Emory College of Arts and Sciences Emory University Atlanta Georgia USA.
JIMD Rep. 2025 Jul 11;66(4):e70037. doi: 10.1002/jmd2.70037. eCollection 2025 Jul.
Classic galactosemia (CG) is a rare inborn error of metabolism with substantial unmet medical need. Early detection, often by population newborn screening, enables immediate and life-long dietary restriction of galactose, which is the current standard of care. This treatment minimizes or prevents the potentially lethal acute symptoms of disease in infants but fails to prevent the long-term developmental complications experienced by most patients later in childhood. Many possible approaches to improved intervention have been proposed, ranging from small molecule inhibitors or effectors to chaperones to DNA or RNA-based gene therapy, among others. Here, we describe the results of a pilot study testing the potential efficacy of GALT+ bone marrow transplantation (BMT) as a candidate intervention in a GALT-null rat model of CG. Specifically, we pre-treated adolescent GALT-null rats with busulfan for myeloablation and then administered major histocompatibility complex (MHC)-matched GFP+ bone marrow cells harvested from either GALT+ or GALT-null donors. Successful engraftment of GALT+ but not GALT-null cells resulted in > 50% wild-type levels of GALT activity in red blood cells (RBC) and normalized RBC galactose-1-phosphate, a biomarker commonly followed in CG patients. However, GALT activity and galactose metabolites in both liver and brain samples remained essentially unchanged, demonstrating that successful GALT+ BMT in adolescent GALT-null rats was not protective of other tissues.
经典型半乳糖血症（CG）是一种罕见的先天性代谢缺陷病，存在大量未满足的医疗需求。通常通过人群新生儿筛查进行早期检测，可立即并终身限制半乳糖饮食，这是目前的标准治疗方法。这种治疗可将婴儿期疾病潜在的致命急性症状降至最低或预防，但无法预防大多数患者在儿童后期出现的长期发育并发症。已经提出了许多改善干预的可能方法，从小分子抑制剂或效应物到伴侣蛋白，再到基于DNA或RNA的基因治疗等等。在这里，我们描述了一项试点研究的结果，该研究测试了GALT+骨髓移植（BMT）作为CG基因缺失大鼠模型候选干预措施的潜在疗效。具体而言，我们用白消安预处理青春期GALT基因缺失大鼠以进行骨髓消融，然后给予从GALT+或GALT基因缺失供体采集的主要组织相容性复合体（MHC）匹配的GFP+骨髓细胞。GALT+细胞而非GALT基因缺失细胞的成功植入导致红细胞（RBC）中GALT活性达到野生型水平的>50%，并使RBC半乳糖-1-磷酸正常化，这是CG患者常用的生物标志物。然而，肝脏和脑样本中的GALT活性和半乳糖代谢物基本保持不变，表明青春期GALT基因缺失大鼠中成功的GALT+ BMT对其他组织没有保护作用。
